Polycaprolactone (PCL) is among the most common and well-studied bioresorbable polymers. The repeating molecular structure of PCL homopolymer consists of five non-polar methylene groups and a single relatively polar ester group. This high molecular weight polyester is conventionally produced by the ring-opening polymerisation of the cyclic monomer, i.e. ϵ-caprolactone. A catalyst is used to start the polymerisation and an initiator, such as an alcohol, can be used to control the reaction rate and to adjust the average molecular weight. PCL is a semi-crystalline (˜40-50%), strong, ductile and hydrophobic polymer with excellent mechanical characteristics having a low melting point of 60° C. and a glass transition temperature of −60° C.
Poly(ethylene glycol) (PEG) is a biocompatible and highly water soluble (hydrophilic) polymer. Poly(ethylene glycols) are poly(ethylene oxides) containing the repeat unit —CH2CH2O—. PEG is a highly crystalline (˜90-95%) polymer having a low melting point of 60° C. and a glass transition temperature of −55 to −70° C. These difunctional compounds contain hydroxyl end-groups, which can be further reacted and chain extended with diisocyanates or used as initiators for ring-opening polymerisations. PEGs are well-known structural units incorporated into crosslinked polyurethane hydrogels (EP publications EP0016652 and EP0016654) and linear polyurethane hydrogels (PCT publication WO2004029125).
Amphiphilic block copolymers, e.g. PEG-PCL copolymers, have recently attracted attention in the field of medicine and biology as micellar carriers, polymer vesicles and polymer matrices. The triblock copolymer PCL-PEG-PCL has unique phase behaviour in blends and the ability to form polymeric micelle-like core-shell nanostructures in a selective solvent, in which only one block is soluble (J. Polym. Sci. Part A Polym. Chem., 1997, 35, 709-714; Adv. Drug Delivery Rev., 2001, 53, 95-108).
However, the above-mentioned polymers suffer from a number of practical disadvantages. The degradation rate and mechanism appear to depend on a number of factors, such as the chemical structure of the polymer and on the surrounding environmental conditions, such as the degradation media. Two stages have been identified in the degradation process of aliphatic polyesters. Initially, the degradation proceeds by random hydrolytic chain scission of the ester bonds, leading to a decrease in the molecular weight; in the second stage measurable weight loss in addition to chain scission is observed. Another observation is that polycaprolactone degrades much slower than e.g. polylactide. The long degradation time of polycaprolactone (˜24 months) is usually a disadvantage for medical applications.
Patent publication WO2005/068533 discloses biodegradable polyurethane polymers formed of prepolymers of caprolactone and polyethylene glycol, reacted with a diisocyanate. The polymers may be used as a drug delivery vehicle, for example as microspheres. However, this publication does not specifically disclose polymers, where the first prepolymer includes a high molecular weight PEG and the second prepolymer includes a low molecular weight PEG.
Our prior patent publication WO2008/047100 describes bioresorbable caprolactone-polyurethane polymers derived from structural units based on caprolactone, poly(alkylene oxide) and diisocyanate for the sustained delivery of active agents. It is an object of the present invention to provide polymers of this general type in microparticle form suitable for administration to patients.